Tricyclic amino containing compounds for treatment or prevention of symptoms associated with endocrine dysfunction

ABSTRACT

The disclosure provides methods of use of certain compounds that are useful for treating certain symptoms of endocrine disturbances, and in particular those associated with hot flashes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/556,346 filed Nov. 7, 2011, hereby incorporated by reference in itsentirety.

FIELD

The disclosure provides pharmaceutical compositions and methods of useof certain tricyclic amino containing compounds for the prevention ortreatment of symptoms associated with endocrine disturbances typicallyhot flashes.

BACKGROUND

Eighty-five percent of the women in the United States experience hotflashes of some kind as they approach menopause and for the first yearor two after their periods stop. Between 20 and 50% of women continue tohave them for many more years. A hot flash is characterized by a sudden,intense, hot feeling on the face and upper body. Often the hot flash canbe preceded or accompanied by a rapid heartbeat and sweating, nausea,dizziness, anxiety, headache, weakness, or a feeling of suffocation.Some women experience a general, overall uneasy feeling just before thehot flash. A hot flash is generally followed by a flush, leaving thesufferer reddened and perspiring. High intensity hot flashes can resultin the sufferer becoming soaked in perspiration. Lower intensity flashescause merely produce a moist upper lip. A chill often precedes theflash, but can also occur at the conclusion of the flash. When hotflashes occur during the night, they sufferer can't sleep, resulting inpoor concentration, memory problems, irritability and exhaustion duringthe day.

Hot flashes are often due to the hormonal changes of menopause, but canalso be affected by lifestyle and medications. The exact cause of hotflashes is not currently known. Some theories suggest that hot flashesare due to a drop in the body's level of female hormones calledestrogens. A diminished level of estrogen has a direct effect on thehypothalamus, the part of the brain responsible for controllingappetite, sleep cycles, sex hormones, and body temperature. The bodyresponds to reduced levels of estrogen by increasing release ofneurotransmitters from the hypothalamus and these increases inepinephrine, norepinephrine, prostaglandin and serotonin cause the heartto pump faster, the blood vessels in skin to dilate and sweat glandsrelease sweat. Some people's skin temperature can rise six degreesCentigrade during a hot flash. Areas of dilation of blood vessels in theskin are particularly noticeable in those areas near the skin of thehead, face, neck and chest. This skin dilation cause more blood tocirculate in order to radiate off the heat. The sweat glands thenrelease sweat to cool the body off even more. Once the blood vesselsreturn to normal size, the sufferer feels cool again.

Around 85% of women suffer hot flashes during the years immediatelybefore and after menopause, which occurs on average around the age of51. Hot flashes can begin as early as 2 to 3 years prior to the lastmenstrual period, however. The hot flashes can last up to six months orgo as long as after 15 years after the last menstrual period. Onaverage, the hot flashes continue for two years. The frequency ofepisodes varies widely, from a few episodes a year to up to 20 episodesa day. Men can also have hot flashes if their levels of the male sexhormone testosterone drop suddenly and dramatically.

Both men and women can suffer from hot flashes as a side effect ofcancer therapy. Certain drugs such as Tamoxifen (Nolvadex), which isused to treat breast cancer, as well as Lupron (Leuprolide) and Zoladex(Goserelin), which are employed in the therapy of prostate cancer, canlead to heat sensations. Bilateral orchiectomy for prostate cancer ortesticular cancer also affects the hormone system so that patients cansubsequently suffer from hot flashes. Especially in the case of cancerpatients, hormone replacement therapy is often not advised, becausethere is a concern that cancer regrowth can be stimulated.

Symptoms that mimic hot flashes can occur in both men and women who havea tumor of the hypothalamus or pituitary gland, as well as with thosewho have suffered from certain serious infections, such as tuberculosisor HIV, those with alcoholism or those who suffer from thyroiddisorders. Symptoms that are similar to hot flashes also can be a sideeffect of the food additive monosodium glutamate (MSG), or of certainmedications, particularly nitroglycerin, nifedipine, niacin, vancomycinand calcitonin.

Most commonly, Hormone Replacement Therapy (HRT) is believed to be oneof the most effective treatments available to reduce the onset of hotflashes. These hormones can be taken orally, intravenously,transdermally and/or topically, applied in a cream. However HRT has beenassociated with increased risk of heart disease as well as certain kindsof cancers.

In addition to hrt and the other medications noted above, severalnonprescription dietary supplements or herbal remedies have beenpromoted as natural ways to prevent or treat hot flashes. A range of“natural” therapies on a herbal basis including black cohosh,phytoestrogens, flax seed, red clover, vitamin E (D. L. Barton et al.,J. Clin. Oncol. 1998, 16: 495-500), ginseng and evening primrose oilhave been advocated as possible medications (University of WisconsinMedical School, online courses, “Alternatives for Menopausal Symptoms: AReview of the Evidence”; www.cme.wisc.edu/online/menopause). However,not all of these therapies are effective (K. I. Pritchard, TheOncologist, 2001, 6(4), 353-362).

Alternative medications to help decrease the intensity of hot flashesinclude clonidine, lofexidine, methyldopa and sertraline. Othermedications, which have been suggested, are selective serotonin reuptakeinhibitors (SSRIs) such as fluoxetine hydrochloride (Prozac; C.Loprinzi; www.medicine-news.com/articles/pharma/misc/hotflash-es.html)and paroxetine hydrochloride (Paxil; V. Stearns et al., Ann. Oncol.,2000, 11:17-22) as well as venlafaxine hydrochloride (Effexor; C. L.Loprinzi et al., J. Clin. Oncol., 1998, 16: 2377-2381), which is aserotonin and norepinephrine reuptake inhibitor.

Low doses of megestrol acetate have also been shown to reduce thefrequency of hot flashes in both men and women (Loprinzi et al., N.Engl. J. Med. 1994, 331:347-351). Chronic adrenal insufficiency andweight gain can be side effects. Transdermal clonidine has also beenemployed to reduce the frequency and severity of hot flashes (R. M.Goldberg et al., J. Clin. Onc. 1994, 12:155-158); R. M. Goldberg et al.,J. Clin. Oncol. 1994, 12:155-158; L. R. Laufer, Obstet. Gynecol. 1982,60:583-586). However, side effects such as drowsiness, fatigue, andsymptoms of low blood pressure in some patients were observed.

A variety of treatments addressing hot flashes have been proposed. Forexample, US Publication No. 2004/0092519 to Pharmacia & Upjohn describesmethods of treating or preventing hot flashes by administering effectivedose of a compound selected from reboxetine, S,S-reboxetine,pharmaceutically acceptable salts thereof, derivatives thereof, orprodrugs thereof. U.S. Pat. No. 6,165,504 to Barr Labs describes methodsfor treating hot flashes and improving the quality of life of castratedprostatic cancer patients by administration of cyproterone acetate. USPublication No. 2004/0152733 describes the use of duloxetine fortreatment of hot flashes. US Publication No. 2004/0092519 describes theuse of reboxetine for treatment of symptoms of hormonal variation suchas hot flashes. U.S. Pat. No. 6,395,757 describes administration ofglycopyrrolate analogs for treating hot flashes. US Publication No.2007/0281997 describes treatment of hot flashes in subject with prostatedisorder such as prostate cancer being managed with androgen deprivationtherapy using muscarinic receptor antagonists. US Publication No.2007/0015786 describes treatment of hot flashes, impulse controldisorders and personality change due to a general medical conditionusing selective norepinephrine reuptake inhibitors e.g. atomoxetine andracemic reboxetine. US Publication No. 2002/0016283 describes a methodof treating symptoms of hormonal variation, including hot flashes, usingtachykinin receptor antagonist. U.S. Pat. No. 6,310,098 describes amethod of treating symptoms of hormonal variation including hot flashesby administration of a compound which is a ligand of the alpha-2-deltasubunit of a voltage-gated calcium channel.

However, new treatments for prevention or reduction of symptomsassociated with such endocrine disturbances are needed.

SUMMARY

It was surprisingly found that certain tricyclic amino containingcompounds are effective in reducing symptoms associated with endocrinedisturbances, and in particular with those associated with altered orreduced estrogen and progesterone levels. Methods for the treatment orprevention of endocrine disturbances are thus provided, in particularthe reduction of symptoms of endocrine disturbances such as hot flashesassociated with menopause or chemotherapy by treating a host in needthereof. Generally, methods of treating or preventing symptomsassociated with endocrine disturbances in a host are provided thatinclude administering a compound as described herein to the host.

In certain embodiments, the disclosure relates to methods of treating orpreventing hot flashes comprising administering to a subject diagnosedwith, exhibiting symptoms, or at risk of changing hormone levels apharmaceutical composition comprising a compound disclosed herein. Infurther embodiments, the subject is menopausal or perimenopausal womanor the subject is menstruating or expecting to menstruate with a week orthe subject is a woman diagnosed with vulvodynia. In certainembodiments, the subject is a man diagnosed with prostate cancer.

In certain embodiments, the pharmaceutical composition is administeredin combination with another active agent such as an agonist orantagonist of an estrogen receptor or tamoxifen or an antiandrogen orspironolactone, cyproterone, flutamide, nilutamide, bicalutamide,finasteride, or dutasteride.

In certain embodiments, the compound is MSX-122, i.e.,N-(4-((pyrimidin-2-ylamino) methyl)benzyl)-pyrimidin-2-amine orpharmaceutically acceptable salt thereof.

In certain embodiments, the disclosure relates to the use of a compounddisclosed herein in the production of a medicament for the treatment orprevention of hot flashes.

In particular embodiments, the host is suffering from a reduction inestrogen levels due to menopause. In other embodiments, the host issuffering from endocrine disturbances due to administration of a drug,and in particular due to administration of a chemotherapeutic agent. Infurther embodiments, the host is suffering from an endocrine disordersuch as an autoimmune endocrine disease. In specific embodiments, thehost is suffering from Graves disease.

In one embodiment, the disclosure relates to methods for the treatmentor prevention of symptoms associated with endocrine disturbances, and inparticular for the treatment or prevention of hot flashes is providedthat includes administering a compound of Formula I, or apharmaceutically acceptable salt, ester or prodrug thereof to a host inneed thereof:

whereineach K is independently N or CH;Q, T, U, V, W, X, Y and Z are independently selected from H, R, acyl, F,Cl, Br, I, OH, OR, NH₂, NHR, NR₂, SR, SR, S₂R, S—NHR, S₂—NHR, S—NRR′,S₂—NRR′, NHacyl, N(acyl)₂, CO₂H, CO₂R, where R and R′ are independentlyselected from straight chain, branched or cyclic alkyl or aralkylgroups, as well as aryl and heteroaryl groups; andR₁, R₂, R₃, R₄, R₅ and R₆ are independently selected from H, straightchain, branched or cyclic alkyl, aralkyl, aryl heteroaryl, acyl (R(O═C)—and imidoyl (R(NH═C)— or R(NR′═)C—) groups.

Additional compounds of Formula II-VII are provided herein for thetreatment or prevention of symptoms associated with endocrinedisturbances, and in particular for the treatment or prevention of hotflashes.

In one particular embodiment, a method for the treatment or preventionof symptoms associated with endocrine disturbances, and in particularfor the treatment or prevention of hot flashes is provided includingadministering a compound of Formula XVI, or a pharmaceuticallyacceptable salt, ester or prodrug thereof to a host in need thereof:

Typically, the compounds or compositions are administered to a host atrisk of an endocrine disturbance. In certain embodiments, the host is apremenopausal or menopausal female. In other embodiments, the host issuffering from an endocrine disease. In yet other embodiments, the hosthas received a drug treatment, and in particular a chemotherapytreatment within 10 days or within 9 days, or within 8 days or within 7days, or within 6 days, or within 5 days or within 4 days, or within 3days, or within 2 days or within one day or less of receiving thecompound or composition described herein.

In some embodiments, pharmaceutical compositions or methods include atleast one compound of Formulas (I)-(XVII) in combination or alternationwith at least a second active compound. The second active compound canbe a chemotherapeutic, particularly an agent active against a primarytumor. In other embodiments, the second agent is a hormone replacementor hormone supplement. In further embodiments, the second agent is anestrogen receptor agonist.

In certain embodiments, treatment methods disclosed herein contemplateadministering a pharmaceutical composition comprising a compounddisclosed herein to the subject after, before, or during a surgeryselected from a hysterectomy, oophorectomy, partial oophorectomy,unilateral salpingo-oophorectomy, bilaterial salpingo-oophorectomy orcombination thereof.

DETAILED DESCRIPTION OF THE DISCLOSURE

Pharmaceutical compositions and methods for the treatment or preventionof endocrine disturbances are provided, and in particular with thoseassociated with altered or reduced estrogen and progesterone levels suchas thoseresulting in the symptoms of hot flashes. The inventors havefound that certain compounds described herein can prevent or reducethese symptoms.

The compounds described herein were previously identified as chemokinereceptor modulators. Chemokines are a superfamily of small cytokinesthat induce, through their interaction with G-protein-coupled receptors,cytoskeletal rearrangements and directional migration of several celltypes. These secreted proteins act in a coordinated fashion withcell-surface proteins to direct the homing of various subsets of cellsto specific anatomical sites (Morales, et al. (1999) Proc Natl Acad SciUSA 96: 14470-14475; Homey, B., et al. (2000) J Immunol 164: 3465-3470;Peled, et al. (1999) Science 283: 845-848; Forster, et al. (1999) Cell99: 23-33).

Chemokines are considered to be principal mediators in the initiationand maintenance of inflammation. They have also been found to play animportant role in the regulation of endothelial cell function, includingproliferation, migration and differentiation during angiogenesis andre-endothelialization after injury (Gupta et al. (1998) J Biol Chem,7:4282-4287).

The chemokine receptor, CXCR4, is known in viral research as a majorcoreceptor for the entry of T cell line-tropic HIV (Feng, et al. (1996)Science 272: 872-877; Davis, et al. (1997) J Exp Med 186: 1793-1798;Zaitseva, et al. (1997) Nat Med 3: 1369-1375; Sanchez, et al. (1997) JBiol Chem 272: 27529-27531). T Stromal cell derived factor 1 (SDF-1) isa chemokine that interacts specifically with CXCR4. When SDF-1 binds toCXCR4, CXCR4 activates Gα_(i)-protein-mediated signaling (pertussistoxin-sensitive), including downstream kinase pathways such as Ras/MAPKinases and phosphatidylinositol 3-kinase (PI3K)/Akt in lymphocyte,megakaryocytes, and hematopoietic stem cells (Bleul, et al. (1996)Nature 382: 829-833; Deng, et al. (1997) Nature 388: 296-300; Kijowski,et al. (2001) Stem Cells 19: 453-466; Majka, et al. (2001) Folia.Histochem. Cytobiol. 39: 235-244; Sotsios, et al. (1999) J. Immunol.163: 5954-5963; Vlahakis, et al. (2002) J. Immunol. 169: 5546-5554).

Compounds targeting CXCR4 have been developed primarily for treatment ofHIV because CXCR4 is a major coreceptor for T-tropic HIV infection.Peptide antagonists of CXCR4 receptors have been disclosed. Tamamura etal reported the identification of a specific peptide-based CXCR4inhibitor, T140. T140 is a 14-residue peptide that possesses anti-HIVactivity and antagonism of T cell line-tropic HIV-1 entry among allantagonists of CXCR4 (Tamamura, et al. (1998) Biochem. Biophys. Res.Commun. 253: 877-882). Other peptide-based antagonists have also beendisclosed. For example, European Patent Publication Nos. 1 286 684 and 1061 944 to the University Of British Columbia cover methods of treatmentof diseases, including metastasis, using modified peptide CXCR4antagonists derived from the native SDF-1 ligand. PCT Publication No. WO04/020462 to Takeda Chemical Industries, Ltd. provides peptide CXCR4antagonists for treatment and prevention of breast cancer and chronicrheumatoid arthritis. U.S. Patent Application No. 2004/0132642 to theU.S. Dept. of Health & Human Services in part covers methods ofinhibiting metastasis or growth of a tumor cell with a polypeptide CXCR4inhibitor. Additionally, the metal-chelating cyclams and bicyclamsrepresent one of the few reported non-peptide molecules to effectivelyblock CXCR4 (Onuffer and Horuk (2002) Trends Pharmacol Sci 23:459-467.36). One of these non-peptide molecules is AMD3100, whichentered clinical trials as an anti-HIV drug that blocks CXCR4-mediatedviral entry (Donzella, et al. (1998) Nat Med 4: 72-77; Hatse, et al.(2002) FEBS Lett 527: 255-262; Fujii, et al. (2003) Expert Opin InvestigDrugs 12: 185-195; Schols, et al. (1997) Antiviral Res 35: 147-156).

Other nitrogen containing bicyclic molecules have been developed asCXCR4 antagonists. European Patent Publication No. 1 431 290 and PCTPublication No. WO 02/094261 to Kureha Chemical Industry Co., Ltd coverCXCR4 inhibitors that are potentially useful in treating variousdiseases including cancer metastatic disease. Additionally, certaincompounds are described as CXCR4 inhibitors in U.S. Patent PublicationNo. 2004/0254221 to Yamamazi, et al., PCT Publication Nos. WO 00/5672,04/091518, 04/093817 and 04/106493, all to AnorMED, which describe thesecompounds as inhibitors of CXCR4 and/or CCR5 receptors and suggest thatthese are active as antivirals, particularly against infections oftarget cells by a human immunodeficiency virus (HIV), cancers, withblood cell production and certain inflammatory conditions.

U.S. Patent Publication No. 2007/0054930 to Shim, et al. providescertain compounds that are CXCR4 inhibitors for the treatment ofproliferative conditions mediated by CXCR4 receptors, particularly formetastasis.

Active Compound, and Physiologically Acceptable Salts and ProdrugsThereof

In a first principal embodiment, a compound of Formula I, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereineach K is independently N or CH;Q, T, U, V, W, X, Y and Z are independently selected from H, R, acyl, F,Cl, Br, I, OH, OR, NH₂, NHR, NR₂, SR, SR, S₂R, S—NHR, S₂—NHR, S—NRR′,S₂—NRR′, NHacyl, N(acyl)₂, CO₂H, CO₂R, where R and R′ are independentlyselected from straight chain, branched or cyclic alkyl or aralkylgroups, as well as aryl and heteroaryl groups; andR₁, R₂, R₃, R₄, R₅ and R₆ are independently selected from H, straightchain, branched or cyclic alkyl, aralkyl, aryl heteroaryl, acyl (R(O═C)—and imidoyl (R(NH═C)— or R(NR′═)C—) groups.

In one subembodiment of Formula I, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

Zou et al. (Zou, et al. (2003) Acta Cryst. E59: online 1312-o1313)described the synthesis of a potentially tetradentate ligand,1,4-bis-(pyridine-2-aminomethyl)benzene. Zou described this compound asa potential ligand for metal ions.

In a subembodiment, a compound of Formula I-1 to I-10, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereinQ, T, U, V, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In another sub-embodiment, a compound of Formula I-11 to I-20, or apharmaceutically acceptable salt, ester or prodrug, is provided:

whereinQ, T, U, V, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In a second principal embodiment, the disclosure provides a compound ofFormula IIa or IIb, or a pharmaceutically acceptable salt, ester orprodrug thereof:

whereineach K is independently N or CH;Q, T, U, V, W, X, Y and Z are as defined above;A and B are one and two atom tethers independently selected from —CR═,—CR₃R₄—, —CR3=, —N═, —O—, —NR₃—, —S—, —CR₃═CR₄—, —CR₃R₄—CR₅R₆—, —CR₃═N—,—CR₃R₄—NR₅—, —N═CR₃—, and —NR₃—CR₄R₅—;-D-E- and -G-J- are independently either —NR₃—CR₄— or —N═C—; andR₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are independently selected from H,straight chain, branched or cyclic alkyl, aralkyl, aryl heteroaryl acyl(R(O═C)— and imidoyl (R(NH═C)— orR(NR′═)C—) groups.

In one subembodiment of Formula II, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

In a subembodiment, the disclosure provides a compound of Formula II-1to II-18, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereinQ, T, U, V, W, X, Y and Z are as defined above;A and -D-E- are as defined above; andR₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above.

In another subembodiment, the disclosure provides a compound of FormulaII-19 through II-30, or a pharmaceutically acceptable salt, ester orprodrug thereof:

whereinQ, T, U, V, W, X, Y and Z are as defined above;A, B, -D-E- and -G-J- are as defined above; andR₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above.

In a third principal embodiment, a compound of Formula III, or apharmaceutically acceptable salt, ester or prodrug thereof:

whereineach K is independently N or CH;Q, T, U, V, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In one subembodiment of Formula III, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

Reyes et al. (Reyes, et al. (2002) Tetrahedron 58:8573-8579) describedthe synthesis of certain polyamines from starting pyridinium N-aminides.No specific functions were attributed to these compounds.

In a subembodiment, a compound of Formula III-1 through III-10, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereinQ, T, U, V, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In another subembodiment, a compound of Formula III-11 through III-20,or a pharmaceutically acceptable salt, ester or prodrug thereof, isprovided:

whereinQ, T, U, V, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In an fourth principal embodiment, the disclosure provides a compound ofFormula IVa or IVb, or a pharmaceutically acceptable salt, ester orprodrug thereof:

whereineach K is independently N or CH;Q, T, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above.

In one subembodiment of Formula IVa or IVb, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

In one subembodiment, the disclosure provides a compound of Formula IV-1to IV-12, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereinQ, T, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and -D-E- are as defined above.

In another subembodiment, compounds of the Formula IV-13 to IV-20, or apharmaceutically acceptable salt, ester or prodrug thereof, areprovided:

whereinQ, T, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA, B, -D-E- and -G-J- are as defined above.

In an fifth principal embodiment, a compound of Formula Va, Vb, or Vc ora pharmaceutically acceptable salt, ester or prodrug thereof, isprovided:

whereineach K is independently N or CH;Q, T, U, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In one subembodiment of Formula Va-c, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

In one subembodiment, a compound of Formula V-1 through V-3, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereineach K is independently N or CH;Q, T, U, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In another subembodiment, a compound of Formula V-4 through V-9, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereineach K is independently N or CH;Q, T, U, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In an sixth principal embodiment, the disclosure provides a compound ofFormula VIa or VIb, or a pharmaceutically acceptable salt, ester orprodrug thereof:

whereineach K is independently N or CH;Q, T, U, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above.

In one subembodiment of Formula VIa or b, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

In one subembodiment, a compound of Formula VI-1 to VI-6, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereinQ, T, U, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and -D-E- are as defined above.

In another subembodiment, a compound of Formula VI-7 to VI-10, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereinQ, T, U, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above.

In an seventh principal embodiment, the disclosure provides a compoundof Formula VII, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereineach K is independently N or CH;U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅ and R₆ are as defined above; andM is O, S or NR₃.

In one subembodiment of Formula VII, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

In one subembodiment, a compound of Formula VII-1 to VII-10, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereinU, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅ and R₆ are as defined above; andM is O, S or NR₃.

In another subembodiment, a compound of Formula VII-11 to VII-20, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereinU, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅ and R₆ are as defined above; andM is O, S or NR₃.

In an eight principal embodiment, the disclosure provides a compound ofFormula VIIIa or VIIIb, or a pharmaceutically acceptable salt, ester orprodrug thereof:

whereineach K is independently N or CH;U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above; andM is O, S or NR₃.

In one subembodiment of Formula VIIIa or b, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

In a subembodiment, a compound of Formula VIII-1 to VIII-12, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereinM, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and -D-E- are as defined above.

In another subembodiment, a compound of Formula VIII-13 to VIII-20, or apharmaceutically acceptable salt, ester or prodrug thereof, is provided:

whereinM, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA, B, -D-E- and -G-J- are as defined above.

In a ninth principal embodiment, the disclosure provides a compound ofFormula IX, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereineach K is independently N or CH;W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅ and R₆ are as defined above;A* is independently selected from the group consisting of formulas a-g:

andM is O, S or NR₃.

In one subembodiment, a compound of Formula IX-1 to IX-12 is provided,or a pharmaceutically acceptable salt, ester or prodrug thereof:

whereinW, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In another subembodiment, a compound of Formula IX-13 to IX-24 isprovided, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereinM, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In yet another subembodiment, a compound of Formula IX-25 to IX-36 isprovided, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereinM, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In a tenth principal embodiment, the disclosure provides a compound ofFormula X, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereineach K is independently N or CH;W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above; andA* is as defined above; andM is as defined above.

In one subembodiment, a compound of Formula X-1 to X-14 is provided, ora pharmaceutically acceptable salt, ester or prodrug thereof:

whereinM, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above.

In another subembodiment, a compound of Formula X-15 to X-28 isprovided, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereinM, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above.

In yet another subembodiment, a compound of Formula X-29 to X-38 isprovided, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereinM, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above.

In an eleventh principal embodiment, the disclosure provides a compoundof Formula XI, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereineach K is independently N or CH;Q, T, U, V, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In one subembodiment of Formula XI, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

In one subembodiment, a compound of Formula XI-1 to XI-6 is provided, ora pharmaceutically acceptable salt, ester or prodrug thereof:

whereinQ, T, U, V, W, X, Y and Z are as defined above; andR₁, R₂, R₃, R₄, R₅ and R₆ are as defined above.

In a twelfth principal embodiment, the disclosure provides a compound ofFormula XII, or a pharmaceutically acceptable salt, ester or prodrugthereof:

whereineach K is independently N or CH;Q, T, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above.

In one subembodiment of Formula XII, Y and Z are each hydrogen.Alternatively, W and X are each hydrogen. In yet another subembodiment,W, X, Y and Z are all hydrogen.

In one subembodiment, a compound of Formula XII-1 to XII-5 is provided,or a pharmaceutically acceptable salt, ester or prodrug thereof:

whereinQ, T, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined above; andA and B and -D-E- and -G-J- are as defined above.

In a thirteenth principal embodiment, a compound of Formula XIII, or apharmaceutically acceptable salt, ester or prodrug thereof:

whereinK, Q, T, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅ and R₆ are as defined above; and“spacer” is independently a bond, straight chained or branched C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₁-C₅ alkoxy, C₂-C₅ alkenoxy, andC₂-C₅ alkynoxy wherein the alkyl group can be substituted by aheteroatom (such as N, O or S) for example —CH₂—OCH₂—, —CH₂CH₂—OCH₂—,—CH₂CH₂—OCH₂CH₂—, —CH₂—OCH₂CH₂—, —CH₂CH₂—OCH₂CH₂CH₂—, —CH₂CH₂CH₂—OCH₂—,—CH₂CH₂CH₂—OCH₂CH₂—, —CH₂CH₂—OCH₂CH₂CH₂—, —(CH₂)_(n)—OH(CH₃)—(CH₂)_(n)—,CH₂—OH(CH₃)—O—CH₂, —(CH₂)n-, —(CH₂)n-CO—, —(CH₂)n-N—, —(CH₂)n-O—,—(CH₂)n-S—, —(CH₂O)—, —(OCH₂)—, —(SCH₂)—, —(CH₂S—), -(aryl-O)—,—(O-aryl)-, -(alkyl-O)—, —(O-alkyl)- wherein n is independently 0, 1, 2,3, 4, 5, 6, 7, 8, 9, or 10.

In a fourteenth principal embodiment, a compound of Formula XIVa orXIVb, or a pharmaceutically acceptable salt, ester or prodrug thereof:

whereinK, Q, T, U, V, W, X, Y and Z are as defined above;R₁, R₂, R₃, R₄, R₅ and R₆ are as defined above;“spacer” is as defined above; and“heterocycle” and “heteroaromatic” are as defined herein.

In one particular embodiment, a compound of Formula XV, or apharmaceutically acceptable salt, ester or prodrug thereof:

In a particular subembodiment, the compound is a salt of a compound ofFormula XV, particularly a chloride salt.

In another particular embodiment, a compound of Formula XVI, or apharmaceutically acceptable salt, ester or prodrug thereof:

In another particular embodiment, a compound of Formula XVII, or apharmaceutically acceptable salt, ester or prodrug thereof:

In certain specific embodiments, the compounds are selected from:

IC₅₀ (nM) Compound vs SDF-1 TN-14003 (Ref) MSX- <1 207 AMD-3100 (Ref)MSX- 100 162

MSX- 121 <10

MSX- 122 <10

MSX- 123 <10

MSX- 134 <10

MSX- 135 <10

MSX- 146 <10

MSX- 168 <100

MSX- 169 <100

MSX- 173 >100

MSX- 183 <10

MSX- 195 10

MSX- 200 10

MSX- 205 1

MSX- 125 >10

MSX- 126 >1000

MSX- 127 >1000

MSX- 130 >1000

MSX- 133 >1000

MSX- 137 >1000

MSX- 138 >1000

MSX- 139 10

MSX- 140 10

MSX- 141 >1000

MSX- 142 >1000

MSX- 156s >1000

MSX- 158 >1000

MSX- 159s >1000

MSX- 160 >1000

MSX- 161s >1000

MSX- 163 10

MSX- 164 >100

MSX- 166 >1000

MSX- 167 >100

MSX- 170 <100

MSX- 171 >1000

MSX- 172 10

MSX- 174 >100

MSX- 175 >100

MSX- 176 >100

MSX- 177 >1000

MSX- 178 >1000

MSX- 179 >1000

MSX- 180 ND

MSX- 181 ND

MSX- 182 ND

MSX- 183 <10

MSX- 184 >100

MSX- 185 <100

MSX- 186 >1000

MSX- 189 >1000

MSX- 190 10

MSX- 191 100

MSX- 192 1

MSX- 193 1

MSX- 194 1

MSX- 196 100

MSX- 197 1

MSX- 198 <100

MSX- 199 ND

MSX- 201 1

MSX- 202 1

MSX- 203 1

MSX- 204 1000

MSX- 206 10

MSX- 207 1

MSX- 208 100

MSX- 209 10

MSX- 210 1000

MSX- 211 1000

MSX- 212 100

MSX- 213 >1000

MSX- 214 100

MSX- 219 10

MSX- 221 1

MSX- 222 1

DEFINITIONS

The term alkyl, as used herein, unless otherwise specified, includes butis not limited to a saturated straight, branched, or cyclic, primary,secondary, or tertiary hydrocarbon of typically C₁ to C₁₀, andspecifically includes methyl, trifluoromethyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl,neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl,3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The termoptionally includes substituted alkyl groups. Moieties with which thealkyl group can be substituted are selected from the group consisting ofhydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,either unprotected, or protected as necessary, as known to those skilledin the art, for example, as taught in Greene, et al., Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, herebyincorporated by reference.

Whenever the terms “C₁-C₅ alkyl”, “C₂-C₅ alkenyl”, “C₁-C₅ alkoxy”,“C₂-C₅ alkenoxy”, “C₂-C₅ alkynyl”, and “C₂-C₅ alkynoxy” are used, theseare considered to include, independently, each member of the group, suchthat, for example, C₁-C₅ alkyl includes straight, branched and whereappropriate cyclic C₁, C₂, C₃, C₄ and C₅ alkyl functionalities; C₂-C₅alkenyl includes straight, branched, and where appropriate cyclic C₂,C₃, C₄ and C₅ alkenyl functionalities; C₁-C₅ alkoxy includes straight,branched, and where appropriate cyclic C₁, C₂, C₃, C₄ and C₅ alkoxyfunctionalities; C₂-C₅ alkenoxy includes straight, branched, and whereappropriate cyclic C₂, C₃, C₄ and C₅ alkenoxy functionalities; C₂-C₅alkynyl includes straight, branched and where appropriate cyclic C₁, C₂,C₃, C₄ and C₅ alkynyl functionalities; and C₂-C₅ alkynoxy includesstraight, branched, and where appropriate cyclic C₂, C₃, C₄ and C₅alkynoxy functionalities.

The term lower alkyl, as used herein, and unless otherwise specified,includes a C₁ to C₄ saturated straight, branched, or if appropriate, acyclic (for example, cyclopropyl) alkyl group, optionally includingsubstituted forms. Unless otherwise specifically stated in thisapplication, when alkyl is a suitable moiety, lower alkyl is preferred.Similarly, when alkyl or lower alkyl is a suitable moiety, unsubstitutedalkyl or lower alkyl is preferred.

The term alkylamino or arylamino refers to an amino group that has oneor two alkyl or aryl substituents, respectively.

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis.

The term aryl, as used herein, and unless otherwise specified, refers tophenyl, biphenyl, or naphthyl, and preferably phenyl. The term includesboth substituted and unsubstituted moieties. The aryl group can besubstituted with any desired substituent that does not adversely affectthe key biological properties, including but not limited to moietiesselected from the group consisting of hydroxyl, thiol, amino,alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,halo (F, Cl, I, Br), carboxy, ester, acyl, alkyl, alkenyl, alkynyl,sulfate, phosphoric acid, phosphonic acid, phosphate, or phosphonate,either unprotected, or protected as necessary, as known to those skilledin the art, for example, as taught in Greene, et al., Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The term alkaryl or alkylaryl refers to an alkyl group with an arylsubstituent. The term aralkyl or arylalkyl refers to an aryl group withan alkyl substituent.

The term halo, as used herein, includes chloro, bromo, iodo, and fluoro.

The term acyl refers to a carboxylic acid ester in which thenon-carbonyl moiety of the ester group is selected from straight,branched, or cyclic alkyl or lower alkyl, alkoxyalkyl includingmethoxymethyl, aralkyl including benzyl, aryloxyalkyl such asphenoxymethyl, aryl including phenyl optionally substituted withhalogen, C₁ to C₄ alkyl or C₁ to C₄ alkoxy, sulfonate esters such asalkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di ortriphosphate ester, trityl or monomethoxytrityl, substituted benzyl,trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. Arylgroups in the esters optimally comprise a phenyl group. The term “loweracyl” refers to an acyl group in which the non-carbonyl moiety is loweralkyl.

The term “pharmaceutically acceptable salt, ester or prodrug” is usedthroughout the specification to describe any pharmaceutically acceptableform (such as an ester, phosphate ester, salt of an ester or a relatedgroup) of a compound which, upon administration to a patient, providesthe compound described in the specification. Pharmaceutically acceptablesalts include those derived from pharmaceutically acceptable inorganicor organic bases and acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluensulfonic acid, salicylic acid, malic acid,maleic acid, succinic acid, tartaric acid, citric acid and the like.Suitable salts include those derived from alkali metals such aspotassium and sodium, alkaline earth metals such as calcium andmagnesium, among numerous other acids well known in the art.Pharmaceutically acceptable “prodrugs” can refer to a compound that ismetabolized, for example hydrolyzed or oxidized, in the host to form thecompound of the present disclosure. Typical examples of prodrugs includecompounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound.

The term “heterocyclic” refers to a nonaromatic cyclic group that may bepartially or fully saturated and wherein there is at least oneheteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.The term heteroaryl or heteroaromatic, as used herein, refers to anaromatic that includes at least one sulfur, oxygen, nitrogen orphosphorus in the aromatic ring. Nonlimiting examples of heterocylicsand heteroaromatics are pyrrolidinyl, tetrahydrofuryl, piperazinyl,piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl, imidazolyl,pyrrolinyl, pyrazolinyl, indolinyl, dioxolanyl, or 1,4-dioxanyl.aziridinyl, furyl, furanyl, pyridyl, pyrimidinyl, benzoxazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, indazolyl,1,3,5-triazinyl, thienyl, tetrazolyl, benzofuranyl, quinolyl,isoquinolyl, benzothienyl, isobenzofuryl, indolyl, isoindolyl,benzimidazolyl, purine, carbazolyl, oxazolyl, thiazolyl, benzothiazolyl,isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl,cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, pyrazole,1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, thiazine, pyridazine,benzothiophenyl, isopyrrole, thiophene, pyrazine, or pteridinyl whereinsaid heteroaryl or heterocyclic group can be optionally substituted withone or more substituent selected from the group consisting of halogen,haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido,hydroxyl, acyl, amino, alkylamino, dialkylamino, arylamino, alkoxy,aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, or phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., “Protective Groups in Organic Synthesis,” John Wileyand Sons, Second Edition, 1991, hereby incorporated by reference.Heterocycle and heteraromatic groups include purine and pyrimidines.

Functional oxygen and nitrogen groups on the heteroaryl group can beprotected as necessary or desired. Suitable protecting groups are wellknown to those skilled in the art, and include trimethylsilyl,dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl,trityl or substituted trityl, alkyl groups, acycl groups such as acetyland propionyl, methanesulfonyl, and p-toluenelsulfonyl.

The term purine or pyrimidine includes, but is not limited to, adenine,N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl, aryl,alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine,N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, N⁶-thioalkyl purine, N²-alkylpurines, N²-alkyl-6-thiopurines,thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine,including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil,5-halouracil, including 5-fluorouracil, C⁵-alkylpyrimidines,C⁵-benzylpyrimidines, C⁵-halopyrimidines, C⁵-vinylpyrimidine,C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine,C⁵-amidopyrimidine, C⁵-cyanopyrimidine, C⁵-nitropyrimidine,C⁵-aminopyrimidine, N²-alkylpurines, N²-alkyl-6-thiopurines,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, butare not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine,and 6-chloropurine.

Processes for the Preparation of Active Compounds

General Methods.

¹H NMR or ¹³C NMR spectra were recorded either on 400 MHz or 100 MHzINOVA Spectrometer or 600 MHz or 150 MHz INOVA Spectrometer. The spectraobtained were referenced to the residual solvent peak. They wererecorded in deuterated chloroform, dimethyl sulfoxide-d6, deuteriumoxide or acetone-d6. Melting points were taken on a Thomas Hoovercapillary melting point apparatus and are uncorrected. Low-resolution EImass spectra were recorded on a JEOL spectrometer. Element analyses wereperformed by Atlantic Mircolab (Norcross, Ga.). Flash columnchromatography was performed using Scientific Absorbent IncorporatedSilica Gel 60. Analytical thin layer chromatography (TLC) was performedon precoated glass backed plates from Scientific Adsorbents Incorporated(Silica Gel 60 F₂₅₄). Plates were visualized using ultraviolet or iodinevapors or phosphomolybdic acid (PMA).

Six different methods were used to prepare the compounds of thedisclosure and the characterization data were listed in Table 1.

Method A: Nucleophilic Addition Between Amines and Cyanamides.

This method is performed according to a modified literature procedure(Braun, et al. (1938) J. Am. Chem. Soc. 3: 146-149). 1.0 eq. of diaminedihydrohalide and 3.0 eq. of cyanamide in absolute ethanol were stirredtogether under refluxing for hours. The solvent was removed underreducing pressure to get the crude salt which was purified byrecrystallization in methanol.

Method B: Addition-Elimination Between Amines and Methyl MercaptoDerivatives.

This method is almost similar to a literature procedure (Linton, et al.(2001) J. Org. Chem. 66(22): 7313-7319). 1.0 eq. of diamine and 2.0 eq.methyl mercapto hydrohalide derivatives were dissolved in methanol. Acondenser equipped with a NaOH trap at the top was attached. Afterrefluxing for hours, the solution was reduced to minimal volume underreduced pressure. Ethyl either was added to produce white precipitate.This was recrystallized in hot methanol to give pure product.

Method C: Condensation Between Aldehydes/Ketones and Amino Guanidines toGive Guanylhydrozone Derivatives.

This method is modified from the literature procedure (Murdock, et al.(1982) J. Med. Chem. 25:505-518). A mixture of 1.0 eq. dialdehyde/ketoneand 2.0 eq. amino guanidine hydrohalides in ethanol was heated underreflux for hours. The mixture was cooled to room temperature andfiltered to give the guanylhydrozone hydrohalides.

Method D: Reductive Amination Between Aldehydes/Ketones and Amines

(Abdel-Magid, et al. (1996) J. Org. Chem. 61:3849-3862). 1.0 eq.dialdehydes or ketones and 2.0 eq. amines were mixed in1,2-dichloroethane and then treated with 3.0 eq. sodiumtriacetoxyborohydride (1.0-2.0 mol eq. acetic acid may also be added inreactions of ketones). The mixture was stirred at room temperature underan argon or nitrogen atmosphere for hours until the disappearance of thereactants in TLC plates. The reaction mixture was quenched by adding 1 NNaOH, and the product was extracted by ethyl ether, washed by Brine anddried by anhydrous MgSO₄. The solvent was evaporated to give the crudefree base which could be purified by chromatography. The free basedissolved in ethanolic hydrochloride or tartaric acid to give the saltswhich usually can recrystallize from MeOH/Et₂O.

Method E: Reduction of Amides

(Micovic and Mihailovic (1953) J. Org. Chem. 18:1190). The amides couldbe prepared from the corresponding carboxylic acid or carboxylicchlorides. A mixture of carboxylic acid and thionyl chloride wasrefluxed for hours in an anhydrous system with a condenser equipped witha NaOH trap at the top. The excess thionyl chloride was removed underreduced pressure to get the carboxylic chloride. The carboxylic chloridewas dissolved in dichloromethane following the addition of 2.0 eq. amineand 3 eq. pyridine. The mixture was stirred at room temperature untilthe disappearance of the reactants in the TLC plates. The solvent wasremoved under reduced pressure to get the crude amides which can bepurified by chromatography.

The mixture of 1 eq. amide and 1.9 eq. LiAlH₄ in THF was refluxed untilthe disappearance of the amide from TLC plates. Then the solution wasquenched with the addition of water and 15% NaOH aqueous as described inlit.5 and extracted with ethyl ether, dried over MgSO₄. Removal of thesolvent gave the free amine product which can be purified by thechromatography. The free base dissolved in ethanolic hydrochloride ortartaric acid to give the salts which usually can recrystallize fromMeOH/Et₂O.

Method F: Nucleophilic Substitution of Halides with Amines.

A mixture of 1.0 eq. halides, 2.0 eq. amines and 3 eq. pyridine inethanol was refluxed for hours until the disappearance of the reactants.The solution was condensed and extracted with ethyl ether, washed withbrine, dried with MgSO₄. Removal of the solvent gave the free amineproduct which can be purified by the chromatography. The free basedissolved in ethanolic hydrochloride or tartaric acid to give the saltswhich usually can recrystallize from MeOH/Et₂O.

TABLE 1 CHARACTERIZATION DATA FOR THE PREPARED COMPOUNDS MS (ESI+): m/z(M⁺) M.p. Element Analysis Found Entry Structure ¹HNMR/¹³CNMR (° C.)Found (Calcd.) (Calcd.) WZ1S

D₂O: 600 Mz 1H: 7.40 (4H, s) 13C: 159.019, 136.364, 129.981 302-304(dec) C₈H₁₄Cl₂N₆ C: 36.34 (36.24); H: 5.34 (5.32); N: 31.76 (31.70) Cl:26.70 (26.74) WZ3S

DMSO: 400 Mz 1H: 8.66 (2H, s); 7.6- 8.6 (4H, br); 7.31 (4H, s); 4.36(4H, s); 3.60 (8H, s) 13C: 159.31, 136.50, 127.53, 45.06, 42.54 294-296(dec) C₁₄H₂₂I₂N₆ C: 32.06 (31.84) H: 4.35 (4.20) N: 15.77 (15.91) WZ4S

DMSO: 400 Mz 1H: 12.28 (2H, s); 8.21 (2H, s); 7.94 (4H, s); 7.60-8.20(8H, br) 13C: 155.52, 145.98, 135.18, 127.84 316-318 (dec)C₁₀H₁₆Cl₂N₈•0.7H₂O C: 36.07 (36.20); H: 5.23 (5.29); N: 33.42 (33.77);Cl: 21.11 (21.37) WZ5S

DMSO: 400 Mz 1H: 8.08 (2H, s); 7.32 (4H, s); 6.85-7.71 (8H, br); 4.37(4H, s) 13C: 157.12, 136.61, 127.53, 43.65 278-281 (dec) WZ6S

DMSO: 400 Mz 1H: 12.93 (2H, s); 8.3- 9.2 (4H, br); 8.22 (2H, s); 7.92(4H, s); 3.75 (8H, s) 13C: 195.31, 136.50, 127.53, 45.06, 42.54 349-352(dec.) C₁₄H₂₀Br₂N₈ C: 41.19 (40.96) H: 6.35 (6.19) N: 28.32 (28.66) WZ7S

D₂O: 1H (600 MHz): 7.58 (4H, s); 4.37 (4H, s), 3.58 (8H, s); 2.98 (12H,s) 13C (400 MHz): 131.95, 130.81, 52.45, 51.30, 43.45, 41.45 250-252(dec.) C₁₆H₃₈Cl₄N₄O₂ C: 41.75 (41.83) H: 8.32 (8.26) N: 12.17 (11.92)WZ8S

D₂O: 400 Mz 1H: 7.45 (4H, s); 7.24 (4H, t, J = 7.2 Hz); 6.82 (2H, t, J =7.2 Hz); 6.73 (4H, d, J = 7.2 Hz); 4.27 (4H, s); 3.47 (4H, t, J = 6.2Hz); 3.24 (4H, t, J = 6.2 Hz) 320-322 (dec.) C₂₄H₃₂Cl₂N₄ C: 64.42(64.32) H: 7.21 (7.21) N: 12.52 (12.30) WZ8

CDCl3: 1H (600 MHz): 7.29 (4H, s); 7.18 (4H, t, J = 5.2 Hz); 6.71 (2H,t, J = 4.8 Hz); 6.64 (4H, d, J = 6 Hz), 3.81 (4H, s); 3.23 (4H, t, J =3.6 Hz); 2.91 (4H, t, J = 3.6 Hz); 4.12 (2H, br) 13C (400 Mz): 148.64;139.18; 129.38; 128.36; 117.53; 113.13; 53.49; 48.17; 43.65 42-43 WZ9S

D₂O: 400 Mz 1H: 8.87 (4H, d, J = 7.2 Hz); 8.12 (4H, d, J = 7.2 Hz); 7.63(4H, ); 4.66 (4H, ); 4.48 (4H, s) 13C: 151.21; 142.45; 131.84; 131.18;127.47; 51.35; 49.03 244-246 (dec.) C₂₀H₂₆Cl₄N₄0.7H₂O C: 50.60 (50.37)H: 5.74 (5.79) N: 11.49 (11.75) WZ9

CDCl3: 1H (600 Mz): 8.55 (4H, d, J = 5.4 Hz); 7.32 (4H, s); 7.30 (4H, d,J = 5.4 Hz); 3.83 (4H, ); 3.81 (4H, s); 1.73 (2H, s) 13C (400 Mz):149.73; 149.38; 138.72; 128.21; 122.93; 52.84; 51.72 WZ9S

D2O: 600 Mz 1H: 8.87 (4H, d J = 7.2 Hz); 8.12 (4H, d, J = 7.2 Hz); 7.63(4H, s); 4.66 (4H, s); 4.48 (4H, s) C20H26Cl4N4•0.7H2O C: 50.57 (50.37)H: 5.70 (5.79) N: 11.55 (11.75) WZ10S

D₂O: 1H: 600 mHz 8.61 (2H, dd, J = 6 Hz, 1.2 Hz); 8.60 (2H, d, J = 2.4Hz); 7.99 (2H, dt, J = 7.8 Hz, 1.8 Hz); 7.56 (6H, m); 4.39 (4H, s); 4.37(4H, s) 13C: 400 MHz 148.85; 149.82; 139.26; 132.13; 130.81; 127.48;124.83; 50.48; 48.15 318-320 (dec.) C₂₀H₂₄Cl₂N₄ C: 60.45 (61.38) H: 6.17(6.18) N: 13.89 (14.32) WZ11S

D₂O: 1H: 8.76 (2H, d, J = 4.8 Hz); 8.35 (2H, dt, J = 8 Hz, J = 1.2 Hz);7.91 (2H, d, J = 8 Hz); 7.86 (2H, t, J = 6.4 Hz); 4.62 (4H, s); 4.47(4H, s) 13C: 146.12; 145.53; 144.95; 131.84; 131.07; 127.47; 127.26;51.18; 47.91 236-238 (dec.) C₂₀H₂₆Cl₄N₄0.5H₂O 0.2CH₃COOCH₂CH₃ C: 50.59(50.89) H: 6.08 (5.87) N: 11.46 (11.41) WZ13S

DMSO-D2O: 400 Mz 1H: 7.35 (4H, s), 7.30 (4H, m), 7.10 (6H, m), 4.41 (4H,s) 13C: 137.85, 133.27, 129.88, 129.46, 126.58, 121.70, 51.82 WZ13

CDCl3: 400 Mz 1H; 7.38 (4H, s); 7.22 (4H, t, J = 7.6 Hz); 6.76 (2H, t, J= 7.6 Hz); 7.67 (4H, d, J = 7.6 Hz); 4.35 (4H, s); 4.06 (2H, br) 13C:148.28, 138.65, 129.46, 127.98, 117.78, 113.03, 48.20 126-127 WZ14

CDCl3: 400 Mz 1H: 7.43 (1H, s); 7.36 (3H, m); 7.23 (4H, m); 6.78 (2H, t,J = 7.7 Hz); 6.68 (4H, d, J = 7.7 Hz); 4.07 (2H, s) 13C: 148.26, 140.09,129.44, 129.03, 126.74, 126.54, 117.77, 113.05, 48.42 288.5 (288.4)WZ14S

D2O: 400 Mz 1H: 7.49 (6H, m); 7.37 (3H, m); 7.21 (4H, m); 7.15 (1H, s);4.59 (4H, s) 13C: 133.95, 132.22, 131.68, 131.06, 130.32, 129.86,122.93, 54.6 WZZL- 811

DMSO: 400 Mz 1H: 7.93 (2H, dd, J = 4.8 Hz, 1.2 Hz); 7.34 (2H td, J =12.8 Hz, 2 Hz); 7.25 (4H, s); 6.96 (2H, t, J = 6 Hz), 6.45 (4H, m); 4.41(4H, d, J = 6 Hz) 13C: 158.66, 147.53, 138.84, 136.60, 127.11, 111.67,108.11, 43.93 192-194 290.5 (290.4) WZZL- 811S

D2O: 400 Mz 1H: 7.89 (2H, td, J = 8.4 Hz, 1.6 Hz); 7.79 (2H, d, J = 6.4Hz); 7.43 (4H, s); 7.02 (2H, d, J = 8.4 Hz); 6.90 (2H, t, J = 6.4 Hz);C₁₈H₁₈N₄•2HCl C: 59.28 (59.51) H: 5.44 (5.55) N: 15.19 (15.4) Cl: 19.73(19.52) WZZL- 811TS

DMSO: 1H (600 Mz): 9.07 (2H, br), 7.95 (4H, m); 7.49 (4H, d, J = 8.4Hz); 7.40 (4H, s); 7.11 (6H, m); 6.90 (2H, t, J = 6 Hz); 4.58 (4H, d, J= 5.4 Hz); 3.68 (2H, br) 2.84 (4H, S) 13C (400 Mz): 152.26, 145.40,143.49, 137.82, 136.26, 135.88, 128.12, 127.93, 125.48, 112.42, 44.56,20.78 WZZL- 811LTR

D2O: 400 Mz 1H: 7.88 (2H, t, J = 9.2 Hz); 7.78 (2H, d, J = 6.4 Hz); 7.42(4H, s); 7.02 (2H, d, J = 9.2 Hz); 6.89 (2H, t, J = 6.4 Hz); 4.62 (4H,s); 4.45 (3H, s) 13C: 173.18, 158.52, 147.25, 138.78, 136.79, 127.14,111.69, 108.23, 72.16, 43.94 C₁₈H₁₈N₄•1.75C₄H₆O₆ C: 53.51 (54.3) H: 5.35(5.19) N: 10.11 (10.13) WZ17

DMSO 1H (600 Mz): 7.96 (2H, D, J = 3 Hz): 7.73 (2H, dd, J = 3 Hz, 1.2Hz); 7.32 (4H, s); 7.02 (2H, dd, J = 6 Hz, 4.2 Hz); 6.86 (2 Hz, dq, J =6 Hz, 4.2 Hz, 1.8 Hz); 6.46 (2H, t, 6 Hz); 6.25 (4H, d, J = 6 Hz); 13C(400 Mz): 145.30, 138.79, 137.57, 136.17, 128.00, 124.21, 118.39, 46.42,290.4 (290.4) WZ17S

D2O: 600 Mz 1H: 7.92 (4H, m); 7.67 (4H, m); 7.42 (4H, s); 4.49 (4H, s)13C: 147.21, 136.80, 128.30, 128.25, 127.85, 127.16, 124.26, 45.73 WZ18

CDCl3: 400 Mz 1H: 7.24 (4H, m): 7.19 (4H, s); 6.75 (4H, m); 4.53 (4H,s); 3.02 (6H, s) 13C: 149.90, 137.83, 129.35, 127.16, 116.69, 112.52,56.53, 38.69 WZ19

DMSO 1H (600 Mz): 7.32 (8H, m); 7.28 (4H, s); 7.22 (2H, tt, J = 7.2 Hz,1.2 Hz); 3.66 (4H, s); 3.65 (4H, s); 2.53 (2H, s) 13C (400 Mz): 140.44,139.12, 128.49, 128.33, 128.26, 127.04, 53.24, 53.00 WZ19S

DMSO: 400 Mz 1H: 9.66 (4H, s); 7.59 (4H, s); 7.54 (4H, m); 7.43 (6H, m);4.17 (4H, s); 4.13 (4H, s) WZ20

DMSO 1H (600 Mz): 10.60 (3H, s); 8.71 (3H, s); 7.83 (6H, d, J = 7.8 Hz);7.40 (6H, t, J = 7.8 Hz); 7.15 (3H, t, J = 7.2 Hz); 13C (400 Mz):164.54, 138.94, 135.50, 129.79, 128.75, 124.00, 120.41 318-320 WZ21

CDCl3: 400 Mz 1H: 7.79 (3H, s); 7.62 (2H, d, J = 7.8 Hz), 7.58 (1H, s);7.38 (2H, t, J = 7.8 Hz); 7.18 (5H, m); 6.75 (2H, td, J = 7.8 Hz, 1.2Hz); 6.64 (4H, d, J = 6.6 Hz); 4.41 (4H, s) 13C: 165.97, 147.92, 141.07,138.00, 135.79, 129.80, 129.46, 129.18, 125.03, 124.78, 120.52, 118.02113.15, 48.04 407.6 (407.5) WZ22

CDCl3: 400 Mz 1H: 7.31 (3H, s); 7.18 (6H, m); 6.74 (3H, tt, J = 7.2 Hz,0.8 Hz); 6.63 (6H, dm, J = 7.2 Hz); 4.32 (6H, s); 4.03 (3H, br) 13C:148.24, 140.60, 129.44, 125.66, 117.84, 113.10, 48.42 393.5 (393.5)WZ22S

D2O: 400 Mz 1H: 7.41 (9H, m); 7.16 (3H, s); 6.98 (6H, m); 4.51 (6H, S)WZ23

CDCl3: 1H (600 Mz): 7.41 (4H, m); 7.32 (1H, t, J = 7.2 Hz); 7.22 (2H, t,J = 7.2 Hz); 6.76 (1H, td, J = 7.2 Hz, 1.2 Hz); 6.68 (2H, d, J = 7.2Hz); 4.37 (2H, s); 4.06 (1H, br) 13C (400 Mz): 148.33, 139.62, 129.44,128.81, 127.68, 127.39, 117.72, 113.01, 48.46 34-35 WZ23S

CDCl3: 600 Mz 1H: 11.85 (2H, br); 7.30 (10H, m); 4.36 (2H, s) 13C:134.37, 131.26, 129.86, 129.60, 129.58, 129.44, 128.87, 124.17, 56.18211-212 WZ24

CDCl3: 400 Mz 1H: 7.32 (4H, s); 7.11 (4H, t, J = 7.8 Hz); 6.66 (2H, tm,J = 7.2 Hz); 6.52 (4H, dm, J = 7.6 HZ); 4.48 (2H, m); 1.52 (3H, s); 1.50(3H, s) 13C: 147.51, 143.93, 143.96, 129.30, 126.35, 117.35, 117.36,113.43, 53.31, 53.29, 25.01, 24.91 WZ25

DMSO 1H (600 Mz): 10.13 (2H, s); 7.58 (4H, d, J =7.2 Hz); 7.28 (8H, t, J= 8.1 Hz); 7.02 (2H, t, J = 7.2 Hz); 3.61 (4H, s) 13C (400 Mz): 169.13,139.23, 134.24, 129.05, 128.69, 123.18, 119.10, 42.95 WZ26

CDCl3 1H (600 Mz): 7.20 (8H, m); 6.73 (2H, t, J = 7.2 Hz); 6.64 (4H, d,J = 7.2 Hz); 3.69 (2H, br); 3.42 (4H, t, J = 7.2 Hz); 2.92 (4H, t, J =7.2 Hz) 13C (400 Mz): 148.21, 137.60, 129.49, 129.22, 117.87, 113.18,45.24, 35.32 316.5 (316.4) WZ27

DMSO 1H (600 Mz): 9.86 (2H, s); 7.60 (4H, d, J = 1.8 Hz); 7.28 (4H, t, J= 7.8 Hz); 7.02 (2H, t, J = 7.2 Hz); 2.35 (2H, br); 1.92 (4H, d, J = 6.6Hz); 1.49 (4H, m) 13C (400 Mz): 173.95, 139.43, 128.64, 122.93, 119.04,44.10, 28.29 WZ28

CDCl3 1H (600 Mz): 7.18 (4H, m); 6.69 (2H, tt, 7.8 Hz, 0.6 Hz); 6.60(4H, dd, J = 9.0 Hz, 0.6 Hz); 3.72 (2H, s); 2.99 (4H, d, J = 6.6 Hz);1.92 (4H, d, J = 6.6 Hz); 1.59 (2H, m); 1.03 (4H, m) 13C (400 Mz):148.71, 129.45, 117.19, 112.82, 50.65, 37.94, 30.96 294.5 (294.4) WZ30

CDCl3 1H (600 Mz): 7.26 (4H, m); 6.78 (2H, t, J =7.8 Hz); 7.71 (4H, d, J= 7.8 Hz); 4.28 (4H, s); 3.48 (2H, br); 2.32 (12H, s) 13C (400 Mz):148.44, 134.94; 134.31; 129.53; 117.67; 112.73; 43.70, 16.52 344.7(344.5) WZ31

DMSO: 400 Mz 1H: 10.66 (2H, q, J = 3.2 Hz); 8.24 (2H, m); 7.83 (6H, m);6.67 (2H, q, J = 3.2 Hz); 7.40 (4H, t, J = 7.2 Hz); 7.15 (2H, t, J = 7.2Hz) 13C: 166.84, 139.15, 136.65, 129.79, 128.78, 127.30, 125.57, 124.36,123.88, 119.91, WZ32

CDCl3 1H (600 Mz): 8.15 (2H, q, J = 3.6 Hz); 7.58 (2H, q, J = 3.6 Hz);7.51 (2H, s); 7.23 (4H, t, J = 7.2 Hz); 6.77 (2H, t, J = 7.2 Hz); 6.71(4H, d, J = 7.2 Hz); 4.76 (4H, s); 4.11 (2H, br); 13C (400 Mz): 148.24,134.54, 132.15, 129.56, 126.51, 126.02, 124.58, 117.97, 113.06, 46.75338.5 (338.4) WZ33

CDCl3: 400 Mz 1H: 8.36 (4H, dd, J = 7.2 Hz, 3.2 Hz); 7.55 (4H, dd, J =7.2 Hz, 3.2 Hz); 7.32 (4H, t, J = 8.0 Hz); 6.85 (6H, m); 5.20 (4H, s);3.98 (2H, br) 13C: 148.51, 130.86, 130.53, 129.68, 126.50, 125.13,118.15, 112.94, 41.34 WZ34

CDCl3: 400 Mz 1H: 7.21 (6H, m); 6.76 (2H, t, J = 7.2 Hz); 6.67 (4H, d, J= 8.0 Hz); 4.24 (4H, s); 3.90 (2H, br); 2.32 (6H, s) 13C: 148.42,136.25, 134.21, 130.85, 129.50, 117.82, 113.04, 46.44, 18.68 316.5(316.4) WZ35

CDCl3 1H (600 Mz): 7.44 (2H, m); 7.30 (2H, m); 7.19 (4H, tt, J = 6.6 Hz,1.8 Hz); 6.77 (2H, t, J = 7.8 Hz); 6.68 (4H, d, J = 7.8 Hz); 4.60 (2H,br); 4.40 (4H, s) 13C (400 Mz): 148.13, 137.44, 129.56, 129.51, 128.17,118.21, 113.41, 46.55 WZ35S

DMSO: 400 Mz 1H: 8.25 (4H, br); 7.43 (2H, m); 7.27 (2H, m); 7.16 (4H, t,J = 7.8 Hz); 6.79 (6H, m); 4.39 (4H, s) WZ36

Acetone-d6: 400 Mz 1H: 7.39 (2H, s); 7.33 (4H, s); 6.61 (4H, m); 6.54(4H, m); 4.86 (2H, s); 4.23 (4H, s) 13C: 149.83, 143.17, 140.13, 128.30,116.61, 114.88, 49.11 WZ37

DMSO: 400 Mz 1H: 7.42 (4H, d, J = 9.2 Hz); 7.29 (4H, s); 7.26 (2H, t, J= 6.0 Hz); 6.63 (4H, d, J = 9.2 Hz); 4.30 (4H, d, J = 6.0 Hz) 13C:152.04, 137.68, 133.31, 127.31, 120.54, 112.22, 95.88, 45.41 338.5(338.4) WZ38

DMSO: 400 Mz 1H: 7.97 (4H, d, J =9.2 Hz); 7.88 (2H, t, J = 5.6 Hz); 6.66(4H, d, J = 9.2 Hz); 4.39 (4H, d, J = 5.6 H) 13C: 154.40, 137.42,135.86, 127.42, 126.14, 45.50 WZ40

DMSO 1H (600 Mz): 8.24 (4H, d, J = 3.2 Hz); 7.63 (2H, t, J = 4.0 Hz);7.21 (4H, s); 6.54 (2H, t, J = 3.2 Hz); 4.43 (4H, d, J = 4.0 Hz) 13C(400 Mz): 162.26, 157.95, 138.59, 126.86, 110.15, 43.62 292.4 (292.3)WZ41

CDCl3: 400 Mz 1H: 8.28 (2H, d, J = 4.8 Hz); 7.34 (4H, s); 6.56 (1H, t, J= 4.8 Hz); 5.46 (1H, br); 4.69 (2H, s); 4.62 (2H, d, J = 6.0 Hz); 2.08(1H, s) 13C: 162.27, 157.93, 140.71, 138.74, 126.74, 126.36, 110.14,62.73, 43.65 215.2 (215.3) WZ42

CDCl3 1H (600 Mz): 8.73 (2H, dd, J = 3.6 Hz, 1.2 Hz); 8.08 (2H, dd, J =7.8 Hz, 1.2 Hz), 7.43 (4H, s); 7.37 (4H, m); 7.07 (2H, d, J = 7.8 Hz);6.67 (2H, d, J = 7.8 Hz); 6.6 (2H, t, J = 5.4 Hz); 4.57 (4H, d, J = 5.4Hz) 13C (400 Mz): 147.14, 144.77, 138.43, 138.36, 136.23, 128.84,127.98, 127.94, 121.63, 114.36, 105.32, 47.67 WZ43

CDCl3: 400 Mz 1H: 8.73 (1H, dd, J = 4.0 Hz, 1.6 Hz); 8.08 (1H, dd, J =8.4 Hz, 2.0 Hz); 7.45 (2H, d, J = 7.6 Hz); 7.37 (4H, m); 7.07 (1H, dd, J= 8.4 Hz, 1.6 Hz); 6.63 (2H, d, J = 8.4 Hz); 4.70 (2H, d, J = 6.0 Hz);4.58 (2H, d, J = 6.0 Hz); 1.66 (1H, 6.0 HZ) 13C: 147.14, 144.65, 139.97,138.90, 138.37, 136.26, 128.82, 127.93, 127.76, 127.55, 121.61, 114.41,105.39, 65.32, 47.60 WZ48

CDCl3 1H (600 Mz): 8.10 (2H, d, J = 4.8 Hz); 7.40 (2H, tt, J = 6.0 Hz,1.8 Hz); 7.37 (1H, s); 7.31 (2H, m); 7.28 (1H, s); 6.60 (2H, t, J = 6.0Hz); 6.36 (2H, d, J = 8.4 Hz); 4.89 (2H, t, J = 6.0 Hz); 4.50 (4H, d, J= 6.0 Hz) 13C (400 Mz): 158.77, 148.44, 139.91, 137.67, 129.16, 126.64,126.52, 113.42, 107.08, 46.42 WZ48S

D2O: 600 Mz 1H: 7.83 (2H, td, J = 9 Hz Hz, 1.2 Hz); 7.72 (2H, d, J = 6.6Hz); 7.45 (1H, t, J = 7.8 Hz); 7.36 (2H, d, J = 7.8 Hz); 7.27 (1H, s);6.94 (2H, d, J = 9.0 Hz); 6.87 (2H, t, J = 6.6 Hz); 4.63 (4H, s) WZ49

CDCl3: 400 Mz 1H: 8.03 (1H, d, J = 6.0 Hz); 7.30 (2H, m), 7.61 (1H, td,J = 7.6 Hz, 1.2 Hz); 7.46 (3H, m); 7.37 (2H, m); 6.99 (1H, d, J = 5.6Hz); 5.44 (1H, t, J = 6.0 Hz); 4.82 (2H, d, J = 6.0 Hz), 4.72 (2H, s),1.79 (1H, s) 13C: 155.01, 141.51, 140.31, 139.06, 137.28, 129.96,128.49, 127.60, 127.43, 126.17, 121.54, 118.25, 111.52, 65.30, 45.94WZ50

CDCl3: 400 Mz 1H: 8.03 (2H, d, J = 6.0 Hz); 7.78 (2H, d, J = 8.0 Hz);7.70 (2H, d, J = 8.0 Hz); 7.60 (2H, td, J = 7.6 Hz, 1.6 Hz); 7.45 (2H,td, J = 7.6 Hz, 1.6 Hz); 7.424 (4H, s); 6.98 (2H, d, J = 5.2 Hz); 5.57(2H, br); 4.81 (4H, d, J = 5.2 Hz) 13C: 154.96, 141.33, 138.71, 137.26,130.03, 128.59, 127.42, 126.22, 121.69, 118.28, 111.49, 45.90Additional compounds prepared and tested in cell assays to determineviral inhibition:

MSX-183

MSX-195

MSX-200

MSX-205

MSX-125

MSX-126

MSX-127

MSX-130

MSX-137

MSX-138

MSX-139

MSX-140

MSX-141

MSX-142

MSX-156s

MSX-159s

MSX-161s

MSX-183

MSX-184

MSX-185

MSX-186

MSX-213

MSX-214

MSX-219

MSX-189

MSX-190

MSX-191

MSX-192

MSX-193

MSX-194

MSX-196

MSX-197

MSX-198

MSX-199

MSX-201

MSX-202

MSX-203

MSX-204

MSX-206

MSX-207

MSX-208

MSX-209

MSX-210

MSX-211

MSX-212

MSX-221

MSX-222Formulations

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate. Examples ofpharmaceutically acceptable salts are organic acid addition salts formedwith acids, which form a physiological acceptable anion, for example,tosylate, methanesulfonate, acetate, citrate, malonate, tartarate,succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate.Suitable inorganic salts may also be formed, including, sulfate,nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

The active compound can also be provided as a prodrug, which isconverted into a biologically active form in vivo. A prodrug may beconverted into the parent drug by various mechanisms, includingenzymatic processes and metabolic hydrolysis. Harper, N.J. (1962) inJucker, ed. Progress in Drug Research, 4:221-294; Morozowich et al.(1977) in E. B. Roche ed. Design of Biopharmaceutical Properties throughProdrugs and Analogs, APhA (Acad. Pharm. Sci.); E. B. Roche, ed. (1977)Bioreversible Carriers in Drug in Drug Design, Theory and Application,APhA; H. Bundgaard, ed. (1985) Design of Prodrugs, Elsevier; Wang et al.(1999) Curr. Pharm. Design. 5(4):265-287; Pauletti et al. (1997) Adv.Drug. Delivery Rev. 27:235-256; Mizen et al. (1998) Pharm. Biotech.11:345-365; Gaignault et al. (1996) Pract. Med. Chem. 671-696; M.Asghamejad (2000) in G. L. Amidon, P. I. Lee and E. M. Topp, Eds.,Transport Proc. Pharm. Sys., Marcell Dekker, p. 185-218; Balant et al.(1990) Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53; Balimane andSinko (1999) Adv. Drug Deliv. Rev., 39(1-3):183-209; Browne (1997).Clin. Neuropharm. 20(1): 1-12; Bundgaard (1979) Arch. Pharm. Chemi.86(1): 1-39; H. Bundgaard, ed. (1985) Design of Prodrugs, New York:Elsevier; Fleisher et al. (1996) Adv. Drug Delivery Rev, 19(2): 115-130;Fleisher et al. (1985) Methods Enzymol. 112: 360-81; Farquhar D, et al.(1983) J. Pharm. Sci., 72(3): 324-325; Han, H. K. et al. (2000) AAPSPharm Sci., 2(1): E6; Sadzuka Y. (2000) Curr. Drug Metab., 1:31-48; D.M. Lambert (2000) Eur. J. Pharm. Sci., 11 Suppl 2:S1 5-27; Wang, W. etal. (1999) Curr. Pharm. Des., 5(4):265.

The active compound can also be provided as a lipid prodrug. Nonlimitingexamples of U.S. patents that disclose suitable lipophilic substituentsthat can be covalently incorporated into the compound or in lipophilicpreparations, include U.S. Pat. No. 5,149,794 (Sep. 22, 1992, Yatvin etal.); U.S. Pat. No. 5,194,654 (Mar. 16, 1993, Hostetler et al., U.S.Pat. No. 5,223,263 (Jun. 29, 1993, Hostetler et al.); U.S. Pat. No.5,256,641 (Oct. 26, 1993, Yatvin et al.); U.S. Pat. No. 5,411,947 (May2, 1995, Hostetler et al.); U.S. Pat. No. 5,463,092 (Oct. 31, 1995,Hostetler et al.); U.S. Pat. No. 5,543,389 (Aug. 6, 1996, Yatvin etal.); U.S. Pat. No. 5,543,390 (Aug. 6, 1996, Yatvin et al.); U.S. Pat.No. 5,543,391 (Aug. 6, 1996, Yatvin et al.); and U.S. Pat. No. 5,554,728(Sep. 10, 1996; Basava et al.).

Method of Treatment

The compounds described herein, are particularly useful for thetreatment or prevention of symptoms associated with endocrinedisturbances. The host to be treated is any mammal, preferably a humanpatient and can be either a female or a male, although the ultimatecause of hot flashes can be markedly different for both groups. Forexample, in female patients the hot flash is typically a primary symptomresulting from menopausal hormonal variation. However, the hot flash canalso be drug-induced by anti-estrogen compounds (e.g., tamoxifen,leuprolide acetate, etc.) or surgically-induced by removal ofestrogen-producing tissues (e.g., total abdominal hysterectomy,bilateral salpingo-oophorectomy, etc.). In male patients, the hotflashes typically occur as a side-effect of androgen-dependent therapyfor metastatic prostate cancer. They can be either surgically-induced(e.g., bilateral orchiectomy) or drug-induced (e.g., treatment with agonadotrophin-releasing-hormone agonist, leuprolide acetate, etc.).

In certain embodiments, the host is menopause or a premenopausal (alsoknown as perimenopause) female. Menopause is the point in a woman's lifewhen she has not had a menstrual period for 1 year. For most women,menopause happens around age 50, but every woman's body has its owntimeline. Some women stop having periods in their mid-40s. Otherscontinue well into their 50s. Pre- or premenopause is the process ofchange that leads up to menopause. It can start as early as the late 30sor as late as the early 50s. How long premenopause lasts varies, but itusually lasts from 2 to 8 years. Symptoms associated with premenopauseinclude changes in menstrual cycle, hot flashes, night sweats, vaginaldryness, sleep problems, mood changes (mood swings, sadness, orirritability), pain during sex, more urinary infections, urinaryincontinence, less interest in sex, increase in body fat around thewaist and problems with concentration and memory.

The most well-known effect of menopause is the “hot flash” or “hotflush”, a sudden temporary increase in body temperature: the “flash”sensation in a “hot flash” occurs as the body temperature peaks almostinstantaneously and begins a much slower return to normal. Hot flashescan become so strong that they can raise the body temperature multipledegrees in a very short period of time, and cause the sufferer to feelweak and break out in heavy sweating. Despite the discomfort to theperson, hot flashes are not considered harmful by physicians.

A host can be diagnosed as being in need of treatment by suffering fromat least one symptom associated with an endocrine disturbance such asmenopause. In particular, a host is in need of treatment if the host hassuffered from at least one hot flash, in particular at least one hotflash within the six months prior to treatment. More particularly, thehost has suffered from at least one hot flash within three months, orwithin two months, or within one month prior to treatment.

In some embodiments, the host is suffering from or at risk of sufferingfrom an endocrine disorder. Endocrine disorders include, withoutlimitation, adrenal disorders, including adrenal insufficiencies such asaddison's disease, congenital adrenal hyperplasia (adrenogenitalsyndrome) and mineralocorticoid deficiency, conn's syndrome andcushing's syndrome, adrenogenital syndrome including pheochromocytoma,adrenocortical carcinoma and gra/glucocorticoid remediablealdosteronism; glucose homeostasis disorders such as diabetes mellitus,hypoglycemia (idiopathic hypoglycemia and insulinoma); metabolic bonedisease including osteoporosis, osteitis deformans (paget's disease ofbone), rickets and osteomalacia; pituitary gland disorders includingdiabetes insipidus, hypopituitarism (or panhypopituitarism), pituitarytumors (pituitary adenomas, prolactinoma (or hyperprolactinemia),acromegaly, gigantism and cushing's disease); parathyroid glanddisorders including primary hyperparathyroidism, secondaryhyperparathyroidism, tertiary hyperparathyroidism and hypoparathyroidism(including pseudohypoparathyroidism); sex hormone disorders includingdisorders of sex development or intersex disorders, hermaphroditism,gonadal dysgenesis and androgen insensitivity syndromes; hypogonadismincluding gonadotropin deficiency, kallmann syndrome, klinefeltersyndrome, ovarian failure, testicular failure and turner syndrome;gender identity disorder; delayed or precocious puberty; menstrualfunction or fertility disorders including amenorrhea and polycysticovary syndrome; thyroid disorders including goiter, hyperthyroidism andGraves-basedow disease, hypothyroidism, thyroiditis and thyroid cancer;tumours of the endocrine glands such as multiple endocrine neoplasiatypes 1, 2a and 2b; and autoimmune polyendocrine syndromes. Certainunderlying disorders, such as HIV or certain cancers as described below,can cause endocrine disturbances that lead to symptoms, including hotflashes, in the host suffering from the disorder. In certainembodiments, a method of treatment of a patients suffering from adisorder, such as HIV or certain cancers as described below, that leadsto symptoms of endocrine disorders is provided comprising administeringthe compounds described herein.

In one embodiment, a method of treating or preventing the symptomsassociated with endocrine disturbances is provided that includesadministering an effective amount of a compound of at least one ofFormula (I)-(XVII) to a host in need thereof. In certain embodiments,the host is suffering from premenopausal or menopausal symptoms. Inother embodiments, the host is suffering from an endocrine disorder.

In other embodiments, the host is being treated with a drug, and inparticular is being treated with a chemotherapeutic agent. In certainembodiments, the symptoms include hot flashes. Women and men who havecancers, in particular those stimulated by sex hormones estrogen andandrogen such as breast, uterine and testicular cancers, can get hotflashes as the chemotherapy lowers these body levels. In particularembodiments, the compound is administered to a host at risk of orreceiving a chemotherapeutic treatment. In particular embodiments, thehost is at risk of or receiving a chemotherapeutic treatment within 10days or within 9 days, or within 8 days or within 7 days, or within 6days, or within 5 days or within 4 days, or within 3 days, or within 2days or within one day or less of receiving the compound or composition.

In some embodiments, the compound is administered after achemotherapeutic treatment. In particular embodiments, the compound isadministered at least one hour after to, or at least two hours after, orat least three hours after, or at least four hours after, or at leastfive hours after, or at least six hours after, or at least seven hoursafter, or at least eight hours after, or at least twelve hours after, orat least one day after, the chemotherapeutic treatment.

In some embodiments, the compound is administered prior to orconcomitant with a chemotherapeutic treatment. In particularembodiments, the compound is administered at least one hour prior to, orat least two hours prior to, or at least three hours prior to, or atleast four hours prior to, or at least five hours prior to, or at leastsix hours prior to, or at least seven hours prior to, or at least eighthours prior to, or at least twelve hours prior to, or at least one dayprior to, the chemotherapeutic treatment.

The active materials can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, in liquid or solid form. However, thecompounds are particularly suited to oral delivery.

A nonlimiting example of a dose of the compound will be in the rangefrom about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight perday, more generally 0.1 to about 100 mg per kilogram body weight of therecipient per day. The effective dosage range of the pharmaceuticallyacceptable salts and prodrugs can be calculated based on the weight ofthe parent compound to be delivered. If the salt, ester or prodrugexhibits activity in itself, the effective dosage can be estimated asabove using the weight of the salt, ester or prodrug, or by other meansknown to those skilled in the art.

In one particular embodiment, a method of treating or preventing asymptom of an endocrine disorder, is provided that includesadministering a compound of Formula XVI, or a pharmaceuticallyacceptable salt, ester or prodrug thereof to a host in need thereof:

In a particular subembodiment, the compound is a salt of a compound ofFormula XVI, particularly a chloride salt. In typical embodiments, thesymptom is a hot flash. In most particular embodiments, the host issuffering from or at risk of suffering from recurrent hot flashes.

Pharmaceutical Compositions

In one embodiment, pharmaceutical compositions for use in preventing ortreating a symptom of an endocrine disorder are provided, including atleast one compound of any one of Formulas (I)-(XVII) and apharmaceutically acceptable carrier. In certain embodiments, at least asecond active compound is included in the composition. The second activecompound can be a chemotherapeutic, particularly an agent active againsta primary tumor.

The compound is conveniently administered in unit any suitable dosageform, including but not limited to one containing 7 to 3000 mg,preferably 70 to 1400 mg of active ingredient per unit dosage form. Aoral dosage of 50-1000 mg is usually convenient. Ideally the activeingredient should be administered to achieve peak plasma concentrationsof the active compound of from about 1 uM to 100 mM or from 0.2 to 700uM, or about 1.0 to 10 uM.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcomposition. The active ingredient may be administered at once, or maybe divided into a number of smaller doses to be administered at varyingintervals of time.

A preferred mode of administration of the active compound is oral. Oralcompositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring. When the dosageunit form is a capsule, it can contain, in addition to material of theabove type, a liquid carrier such as a fatty oil. In addition, dosageunit forms can contain various other materials which modify the physicalform of the dosage unit, for example, coatings of sugar, shellac, orother enteric agents.

The compound can be administered as a component of an elixir,suspension, syrup, wafer, chewing gum or the like. A syrup may contain,in addition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors.

The compound or a pharmaceutically acceptable prodrug or salts thereofcan also be mixed with other active materials that do not impair thedesired action, or with materials that supplement the desired action,such as antibiotics, antifungals, anti-inflammatories, or antiviralcompounds, or with additional chemotherapeutic agents. Solutions orsuspensions used for parenteral, intradermal, subcutaneous, or topicalapplication can include the following components: a sterile diluent suchas water for injection, saline solution, fixed oils, polyethyleneglycols, glycerine, propylene glycol or other synthetic solvents;antibacterial agents such as benzyl alcohol or methyl parabens;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parental preparation can be enclosed inampoules, disposable syringes or multiple dose vials made of glass orplastic.

In a typical embodiment, the active compounds are prepared with carriersthat will protect the compound against rapid elimination from the body,such as a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation. If administered intravenously, preferred carriers arephysiological saline or phosphate buffered saline (PBS).

Liposomal suspensions (including liposomes targeted to infected cellswith monoclonal antibodies to viral antigens) are also preferred aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art, for example, as described inU.S. Pat. No. 4,522,811 (which is incorporated herein by reference inits entirety). For example, liposome formulations may be prepared bydissolving appropriate lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent that is thenevaporated, leaving behind a thin film of dried lipid on the surface ofthe container. An aqueous solution of the active compound or itsmonophosphate, diphosphate, and/or triphosphate derivatives is thenintroduced into the container. The container is then swirled by hand tofree lipid material from the sides of the container and to disperselipid aggregates, thereby forming the liposomal suspension.

Combination and Alternation Therapy

In one embodiment, the compounds described herein are administered incombination or alternation with another active compound.

In one embodiment, the compound is administered in combination oralternation with a hormone replacement therapy. In certain embodiments,the compound is administered in combination or alternation with anestrogen and/or a progesterone or progestin.

In one embodiment, the active compound is a compound that is used as achemotherapeutic. The compound provided in combination or alternationcan, for example, be selected from the following list:

13-cis-Retinoic 2-Amino-6- 2-CdA 2- Acid MercaptopurineChlorodeoxyadenosine 5-fluorouracil 5-FU 6-TG 6-Thioguanine6-Mercaptopurine 6-MP Accutane Actinomycin-D Adriamycin Adrucil AgrylinAla-Cort Aldesleukin Alemtuzumab Alitretinoin Alkaban-AQ Alkeran All-Alpha interferon Altretamine transretinoic acid Amethopterin AmifostineAminoglutethimide Anagrelide Anandron Anastrozole ArabinosylcytosineAra-C Aranesp Aredia Arimidex Aromasin Arsenic trioxide AsparaginaseATRA Avastin BCG BCNU Bevacizumab Bexarotene Bicalutamide BiCNUBlenoxane Bleomycin Bortezomib Busulfan Busulfex C225 Calcium CampathCamptosar Camptothecin-11 Leucovorin Capecitabine Carac CarboplatinCarmustine Carmustine wafer Casodex CCNU CDDP CeeNU Cerubidine cetuximabChlorambucil Cisplatin Citrovorum Cladribine Cortisone Factor CosmegenCPT-11 Cyclophosphamide Cytadren Cytarabine Cytarabine Cytosar-U Cytoxanliposomal Dacarbazine Dactinomycin Darbepoetin alfa DaunomycinDaunorubicin Daunorubicin Daunorubicin DaunoXome hydrochloride liposomalDecadron Delta-Cortef Deltasone Denileukin diftitox DepoCytDexamethasone Dexamethasone dexamethasone acetate sodium phosphateDexasone Dexrazoxane DHAD DIC Diodex Docetaxel Doxil DoxorubicinDoxorubicin Droxia DTIC DTIC-Dome liposomal Duralone Efudex EligardEllence Eloxatin Elspar Emcyt Epirubicin Epoetin alfa Erbitux Erwinia L-Estramustine asparaginase Ethyol Etopophos Etoposide Etoposide phosphateEulexin Evista Exemestane Fareston Faslodex Femara FilgrastimFloxuridine Fludara Fludarabine Fluoroplex Fluorouracil FluorouracilFluoxymesterone Flutamide Folinic Acid (cream) FUDR Fulvestrant G-CSFGefitinib Gemcitabine Gemtuzumab Gemzar Gleevec ozogamicin Gliadel waferGlivec GM-CSF Goserelin granulocyte colony Granulocyte HalotestinHerceptin stimulating factor macrophage colony stimulating factorHexadrol Hexalen Hexamethylmelamine HMM Hycamtin Hydrea HydrocortAcetate Hydrocortisone Hydrocortisone Hydrocortisone HydrocortoneHydroxyurea sodium phosphate sodium phosphate succinate IbritumomabIbritumomab Idamycin Idarubicin Tiuxetan Ifex IFN-alpha Ifosfamide IL-2IL-11 Imatinib Imidazole Interferon alfa mesylate Carboxamide InterferonAlfa-2b Interleukin-2 Interleukin-11 Intron A (interferon (PEGconjugate) alfa-2b) Iressa Irinotecan Isotretinoin Kidrolase LanacortL-asparaginase LCR Letrozole Leucovorin Leukeran Leukine LeuprolideLeurocristine Leustatin Liposomal Ara-C Liquid Pred Lomustine L-PAML-Sarcolysin Lupron Lupron Depot Matulane Maxidex MechlorethamineMechlorethamine Medralone Medrol Megace Hydrochlorine MegestrolMegestrol Melphalan Mercaptopurine Acetate Mesna Mesnex MethotrexateMethotrexate Sodium Methylprednisolone Meticorten Mitomycin Mitomycin-CMitoxantrone M-Prednisol MTC MTX Mustargen Mustine Mutamycin MyleranMylocel Mylotarg Navelbine Neosar Neulasta Neumega Neupogen NilandronNilutamide Nitrogen Novaldex Novantrone Mustard Octreotide OctreotideOncospar Oncovin acetate Ontak Onxal Oprevelkin Orapred OrasoneOxaliplatin Paclitaxel Pamidronate Panretin Paraplatin Pediapred PEGInterferon Pegaspargase Pegfilgrastim PEG-INTRON PEG-L-asparaginasePhenylalanine Platinol Platinol-AQ Prednisolone Mustard PrednisonePrelone Procarbazine PROCRIT Proleukin Prolifeprospan PurinetholRaloxifene 20 with Carmustine implant Rheumatrex Rituxan RituximabRoveron-A (interferon α-2a) Rubex Rubidomycin Sandostatin SandostatinLAR hydrochloride Sargramostim Solu-Cortef Solu-Medrol STI-571Streptozocin Tamoxifen Targretin Taxol Taxotere Temodar TemozolomideTeniposide TESPA Thalidomide Thalomid TheraCys Thioguanine ThioguanineThiophosphoamide Thioplex Tabloid Thiotepa TICE Toposar TopotecanToremifene Trastuzumab Tretinoin Trexall Trisenox TSPA VCR VelbanVelcade VePesid Vesanoid Viadur Vinblastine Vinblastine Vincasar PfsVincristine Sulfate Vinorelbine Vinorelbine VLB VM-26 tartrate VP-16Vumon Xeloda Zanosar Zevalin Zinecard Zoladex Zoledronic acid Zometa

In one embodiment, the compounds of the disclosure are administered incombination with another active agent. The compounds can also beadministered concurrently with the other active agent. In this case, thecompounds can be administered in the same formulation or in a separateformulation. There is no requirement that the compounds be administeredin the same manner. For example, the second active agent can beadministered via intravenous injection while the compounds of thedisclosure may be administered orally. In another embodiment, thecompounds of the disclosure are administered in alternation with atleast one other active compound. In a separate embodiment, the compoundsof the disclosure are administered during treatment with achemotherapeutic, such as, for example, an agent listed above, andadministration of the compounds of the disclosure is continued aftercessation of administration of the other active compound. The compoundmay be administered for at least a month, at least two months, at leastfour, six, seven, eight, nine, ten, eleven, twelve months or more toreduce incidence of metastasis.

The compounds of the disclosure can be administered prior to or aftercessation of administration of another active compound. In certaincases, the compounds may be administered before beginning a course oftreatment for primary tumors, for example, to prevent symptomsassociated with endocrine disturbances such as hot flashes. In aseparate embodiment, the compounds can be administered after a course ofchemotherapy to reduce symptoms of endocrine disturbances.

EXAMPLES Example 1 Screening of Small Molecule Compounds with aCompetitive Binding Assay Against Biotinlabeled TN14003

A synthetic 14-mer peptide, TN14003, was previously reported to blockboth SDF-1/CXCR4 mediated invasion in vitro and metastasis in vivo witha high specificity by binding competitively with its ligand SDF-1. Aacompetitive binding assay using biotin-labeled TN14003 andstreptavidin-conjugated rhodamine was developed to determine the bindingefficiency of new chemical entities to the SDF-1 binding domain ofCXCR4. Cells incubated with high affinity compounds show only bluenuclear staining, whereas compounds with low affinity result in stainingCXCR4 (red; rhodamine) as well as the nuclei (blue; cytox blue).Effective concentrations (EC50) for certain compounds were identifiedand EC50 for MSX-122 and AMD3100 were 0.6 and 26 nM, respectively.

Example 2 cAMP Assay

Because the major signaling pathway of CXCR4/SDF-1 involves thepertussis toxin-sensitive G protein Gi, compounds described herein weretested as to whether they inhibited SDF-1/CXCR4-mediated cAMP reduction.The absorption increase at 665 nm was determined by varying theconcentration of SDF-1 (0-200 ng/ml) to determine EC80 to be 150 ng/ml.With pre-treatment of MSX-122 or AMD3100, the effect of SDF-1 on cAMPreduction was blocked significantly in a dose-dependent manner. WhileMSX-122 was effective in counteracting SDF-1 function at concentrationsas low as 10 nM, AMD3100 required almost 1000 nM to significantly blockSDF-1 function.

Example 3 Pharmacokinetics of MSX-122

Oral bioavailability and sustained plasma exposure was consistentlyobserved in multiple species for certain compounds. In an initialpharmacokinetic study in mice, MSX-122 generated sustained blood levelswhen administered both intraperitoneally (IP) and orally. In apharmacokinetic study in rats, the oral absorption seemed to occur veryquickly with an initial Tmax of ˜30 min. and plasma levels remainedabove 100 ng/ml (342 nM) for 10 hours when it was administered at 10mg/kg. In a pharmacokinetic/pharmacodynamic study conducted innon-naïve, female cynomolgus monkeys, MSX-122 was administered orally at1, 5 and 10 mg/kg and resulted in sustained pharmacokinetics with plasmalevels that were relatively dose proportional. The 5 and 10 mg/kg dosesboth generated micromolar plasma concentrations with half lives thatsupport once per day dosing.

Example 4 In Vitro Genotoxicity and Safety

MSX-122 was tested for genotoxicity in an in vitro Ames test(BioReliance Corp., Rockville, Md.) that demonstrated no evidence ofmutagenicity and an in vitro chromosome aberration screening test(BioReliance Corp., Rockville, Md.) using CHO cells treated with MSX-122which showed no statistically significant increase in structural ornumerical chromosome aberrations at any dose level up to the highestdose of 2 mM. Sufficiently scorable cells in the presence of S9 wereavailable for 4 hour treatment and in the absence of S9 for a 20 hourtreatment. Finally, MSX-122 was tested for its potential to interferewith the rapid delayed rectifier current (IKr) in human ventriclesthrough the cardiac potassium channel, hERG since inhibition of IKr hasbeen reported to be the most common cause of cardiac action potentialprolongation by non-cardiac drugs. The resulting data indicate thatMSX-122 and analogs do not exert a significant inhibitory effect on hERGchannel currents (1 μM MSX-122 (WZ40-MS)−0.2% inhibition).

Example 5 Toxicology Studies in Rats and Monkeys

In initial studies, three groups of rats (5 males and 5 females pergroup) were dosed with 0, 250 and 600 mg/kg of MSX-122 orally once perday for 28 days. The pharmacokinetic data show that micromolarconcentrations of MSX-122 were maintained throughout the term of thestudy after day 1, and Cmax values were in the range of 2-4 μg/ml(6.8-13.6 μM). No signs or symptoms of toxicity were observed in any ofthe animals during the study, and no toxicity was observed upontermination from blood serum chemistry or gross necropsy. A 5-day repeatdose study was carried out in two non-naïve cynomolgus monkeys (1 maleand 1 female) and two naïve cynomolgus monkeys (1 male and 1 female)dosed with 1,000 and 2,000 mg/kg, respectively, orally once per day for5 days. No drug-related signs or symptoms of toxicity were observed, andthere were no abnormalities in the resulting blood serum chemistry.Gross necropsy of the animals dosed at 2000 mg/kg also revealed noabnormalities or signs of toxicity. The only observations were loose andwatery stool in a subset of the animals which may have been caused bythe excipients in the formulation. The data showed that micromolarconcentrations of MSX-122 were maintained throughout the term of thestudy with Cmax in the range of 5.1 μM (1.5 μg/ml) to 12 μM (3.5 μg/ml).

Example 6 Treatment of Hot Flashes

An approximately 70 kg 56-year old female with a history of aggressivehigh grade serous carcinomy in her right fallopian tube, a completehysterectomy and bilateral oophorectomy after previous treatments withVEGF-Trap and docetaxel, Carboplatin and taxol and doxil was treatedwith MSX-122, 50 mg/day oral. The woman was suffering from Gravesdisease and had a history of hot flashes. After her third treatment ofMSX-122, she noted that her past history of hot flashes had resolvedgreatly since starting the trial.

What is claimed:
 1. A method of treating hot flashes comprisingadministering a pharmaceutical composition comprising a compound of thefollowing structure

or a pharmaceutically acceptable salt thereof to a subject in needthereof.
 2. The method of claim 1, wherein the subject is menopausal orperimenopausal woman.
 3. The method of claim 1, wherein the subject ismenstruating or expecting to menstruate with a week.
 4. The method ofclaim 1, wherein the subject is a woman diagnosed with vulvodynia. 5.The method of claim 1, wherein the pharmaceutical composition isadministered in combination with another active agent.
 6. The method ofclaim 1, wherein the pharmaceutical composition is administered incombination with an agonist or antagonist of an estrogen receptor. 7.The method of claim 1, wherein the pharmaceutical composition isadministered in combination with tamoxifen.
 8. The method of claim 1,wherein said compound isN-(4-((pyrimidin-2-ylamino)methyl)benzyl)-pyrimidin-2-amine.
 9. Themethod of claim 1, further comprising the step of administering thepharmaceutical composition to the subject after, before, or during asurgery selected from a hysterectomy, oophorectomy, partialoophorectomy, unilateral salpingo-oophorectomy, bilaterialsalpingo-oophorectomy or combination thereof.